title: Serum amyloid A stimulates cultured endothelial cells to migrate and proliferate: inhibition by the multikinase inhibitor BIBF1120.
abstract: In the present study, we tested whether serum amyloid A (SAA) protein, an established biomarker of inflammation, also plays a role in stimulating neovascularization. To evaluate this possibility, human carotid artery endothelial (HCtAE) cells were cultured and cellular migration and the proinflammatory and/or thrombotic activity of SAA (0, 1 or 10 μg/mL) on vascular endothelial cells was verified by determining gene regulation relative to control (in the absence of SAA). Exposure of HCtAE cells to SAA increased expression of the transcription factor nuclear factor-κB (NFKB), tumour necrosis factor (TNF) and pro-coagulative tissue factor (F3), and stimulated phosphorylation of the P65 subunit of the NFKB complex. Enhanced production of TNF and NFKB was paralleled by increased vascular endothelial growth factor (VEGF) mRNA and protein expression, as demonstrated by quantitative polymerase chain reaction, western blotting and ELISA. Administration of 10 μg/mL SAA enhanced endothelial cell migration (1.6-fold vs control), stimulated regrowth of HCtAE cells after mechanical injury (~1.2-fold vs control) and increased endothelial tube formation relative to control after 6 h. The SAA-mediated enhancement of endothelial cell migration, proliferation and tube formation were markedly inhibited by pretreatment of HCtAE cells with the multi-angiokinase receptor inhibitor BIBF1120 (100 nmol/L), although SAA-stimulated gene responses for F3 and NFKB were unaffected by 100 nmol/L BIBF1120 pretreatment. Overall, BIBF1120 inhibited the pro-angiogenic activity of SAA on vascular endothelial cells in this experimental model of inflammation.
authors.affiliation: Discipline of Pathology, University of Sydney, Sydney, New South Wales, Australia.
authors.forename: Xiaoping
authors.initials: X
authors.lastname: Cai
authors.forename: S Ben
authors.initials: SB
authors.lastname: Freedman
authors.forename: Paul K
authors.initials: PK
authors.lastname: Witting
mesh_terms: D002339:Carotid Arteries / Q000187:drug effects / Q000378:metabolism; D002352:Carrier Proteins / Q000235:genetics / Q000378:metabolism; D002465:Cell Movement / Q000187:drug effects / Q000235:genetics*; D049109:Cell Proliferation / Q000187:drug effects; D002478:Cells, Cultured; D042783:Endothelial Cells / Q000187:drug effects / Q000378:metabolism*; D004730:Endothelium, Vascular / Q000187:drug effects / Q000378:metabolism; D005786:Gene Expression Regulation / Q000187:drug effects / Q000235:genetics; D006801:Humans; D007211:Indoles / Q000494:pharmacology*; D007249:Inflammation / Q000235:genetics / Q000378:metabolism; D047908:Intracellular Signaling Peptides and Proteins; D016328:NF-kappa B / Q000235:genetics / Q000378:metabolism; D009363:Neoplasm Proteins / Q000235:genetics / Q000378:metabolism; D009389:Neovascularization, Pathologic / Q000235:genetics / Q000378:metabolism; D010766:Phosphorylation / Q000187:drug effects / Q000235:genetics; D000685:Serum Amyloid A Protein / Q000235:genetics / Q000378:metabolism*; D013925:Thromboplastin / Q000235:genetics / Q000378:metabolism; D014409:Tumor Necrosis Factor-alpha / Q000235:genetics / Q000378:metabolism; D042461:Vascular Endothelial Growth Factor A / Q000235:genetics / Q000378:metabolism
chemical_list: D002352:Carrier Proteins; C484020:HSAJ2425 protein, human; D007211:Indoles; D047908:Intracellular Signaling Peptides and Proteins; D016328:NF-kappa B; D009363:Neoplasm Proteins; D000685:Serum Amyloid A Protein; D014409:Tumor Necrosis Factor-alpha; C467484:VEGFA protein, human; D042461:Vascular Endothelial Growth Factor A; D013925:Thromboplastin; C530716:nintedanib
keywords: acute phase protein; angiogenesis; endothelial cells; inflammation; neo-vascularization; serum amyloid A